One Size Does Not Fit All:
Personalized Treatment of
Patients with Epilepsy
Vikram R. Rao, MD, PhD
University of California, San Francisco, Epilepsy Center,
San Francisco, California
A REPORT FROM THE 67TH ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY (AES 2013)
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Personalized Treatment in Epilepsy

Epilepsy: enduring tendency for recurrent seizures

4th most common neurological disorder; lifetime
prevalence is 1 in 26 individuals.

Evidence for superiority of one antiepileptic drug
(AED) over another is often lacking.

AEDs are chosen based on patient-specific factors:
» Genetic information
» Physical characteristics and comorbid conditions
» Concurrent medications

Individualizing treatment may maximize tolerability,
adherence, and efficacy
Chang BS, Lowenstein DH. N Engl J Med. 2003;349:1257; Fisher RS et al. Epilepsia. 2005;46:470; Institute
of Medicine, 2012; Glauser T et al. Epilepsia. 2013;54:551; French JA, Gazzola DM. Continuum. 2013;19:643
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Pharmacogenomics in Epilepsy
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Pharmacogenomics:
Overview

Pharmacogenomics: use of biomarkers related to a
patient’s genome to guide drug therapy
Chan A et al. Ann Neurol. 2011;70:684
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Pharmacogenomics:
To Avoid Adverse Drug Reactions

HLA-B*1502 allele predicts carbamazepine (CBZ)induced Stevens-Johnson syndrome in patients of
Han Chinese and South Asian ancestry; pretreatment testing recommended in these patients.

HLA-A*3101 allele may be a marker of CBZ-induced
drug reactions in other patient populations.

Avoid sodium channel blockers, such as lamotrigine
(LTG), in syndromes with SCN1A mutation (eg,
Dravet syndrome).

Research is ongoing for markers of valproate (VPA)induced weight gain and vigabatrin retinopathy.
Chung WH et al. Nature. 2004;428:486; McCormack M et al. N Engl J Med. 2011;364:1134; Ozeki T et al. Hum
Mol Genet. 2011;20:1034; Belcastro V et al. Epilepsy Res. 2013;107:1; Kinirons P et al. Epilepsy Res. 2006;70:144
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Pharmacogenomics:
To Predict Favorable Treatment Responses

Some previously medically refractory patients can
achieve seizure freedom with levetiracetam (LEV).
» Genetic basis of these “dramatic responders” is elusive.

Functional variants of cytochrome P-450 enzymes
affect phenytoin (PHT) metabolism.

SCN1A polymorphisms may influence maximum
dose and serum levels of CBZ and PHT.

A patient’s genetic profile may eventually be used to
determine optimal medical therapy, but ethical,
financial, and legal issues abound.
Nicolson A et al. Neurology. 2004;63:568; Lynch JM et al. Epilepsy Res. 2009;83:44; Dibbens et al. Epilepsy Res.
2012;101:277; Aynacioglu AS et al. Br J Clin Pharmacol. 1999;48:409; Chaudhry AS et al. J Pharmacol Exp Ther.
2010;332:599; Tate SK et al. Proc Natl Acad Sci U S A. 2005;102:5507; Tate SK et al. Pharmacogenet Genomics.
2006;16:721; Zimprich F et al. Epilepsia. 2008;49:1108
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Personalizing Drug Delivery
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Personalizing Drug Delivery:
Formulation

Extended-release (ER) AED formulations allow more
gradual systemic absorption vs immediate-release

ER formulations offer several advantages:
» Less variability in serum drug levels
» Lower incidence of peak-dose toxicity
» Increased patient convenience (may favor compliance)

Benefit directly demonstrated for LTG vs ER CBZ

Potential disadvantages of ER formulations:
» Higher cost
» High peak serum levels may be desired when treating seizures
»
with predictable diurnal variation
Shorter “forgiveness period”
Bialer M. CNS Drugs. 2007;21:765; Canger R et al. Acta Neurol Scand. 1990;82:9; Brodie MJ et al. Epilepsy Res.
1999;37:81; Saetre E et al. Epilepsia. 2007;48:1292; Guilhoto LM et al. Epilepsy Behav. 2011;20:334
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Personalizing Drug Delivery:
Route of Administration

Rectal diazepam in solution leads to a more rapid
increase in serum drug levels than rectal
suppositories (basis for Diastat®)

RAMPART study: Intramuscular midazolam is
superior to intravenous (IV) lorazepam for prehospital treatment of status epilepticus
Higher rate of seizure freedom on arrival to hospital:
» Lower rates of hospital/ICU admission
» Issues: difficulty obtaining IV access; shorter half-life of

lorazepam out of refrigeration

Sublingual lorazepam associated with higher rates of
treatment failure compared with rectal diazepam
Knudsen FU. Acta Paediatr Scand. 1977;66:563; Kriel RL et al. Pediatr Neurol. 1999;20:282; Silbergleit R et al. N
Engl J Med. 2012;366:591; Silbergleit R et al. Epilepsia. 2013;54(suppl 6):74; Malu CK et al. J Child Neurol. 2013
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Personalizing Drug Delivery:
Dosing Considerations

Setting (eg, pre-hospital vs hospital; household vs
ambulance)

Clinical urgency (eg, status epilepticus vs self-limited
seizure)

Ease of obtaining IV access

Logistical considerations of particular medications
and formulations (eg, availability, storage
requirements, cost)

Regulatory approval status and extent of data
supporting clinical efficacy
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Cutaneous Drug Reactions
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Cutaneous Drug Reactions:
Epidemiology


Among treatment-related side effects underlying
AED intolerance, rash is one of the most common.
Adverse cutaneous drug reactions (ACDRs) affect
2% of hospitalized patients.
» With AEDs, 15% of patients will develop a rash within
4 weeks of drug initiation.

Risk factors for ACDRs:
» Age
» Number of comorbid conditions
» Polypharmacy
» Immunosuppression
» Female gender (?)
Chung S et al. J Br Epilepsy Assoc. 2007;16:296; Arndt KA, Jick H. JAMA. 1976;235:918; Porter J, Jick H. JAMA.
1977;237:879; Blaszczyk B et al. Pharmacol Rep. 2013;65:399; Liao PJ et al. Int J Clin Pract. 2013;67:576; Todd
G. Dermatol Clin. 2006;24:459
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Cutaneous Drug Reactions:
Clinical Manifestations

Broad spectrum of severity:
» Mild, diffuse, morbiliform rash
life-threatening
multisystem illness

Key factors for initial evaluation:
» Need to determine chronicity, distribution, pattern,
organization, morphology, probable anatomic depth, and
mucosal membrane involvement

Reactions that are likely immunologic:
» Activated T lymphocytes and macrophages can be found in
areas of damaged skin.
Caproni M et al. Br J Dermatol. 2006;154:319
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Cutaneous Drug Reactions:
DRESS

Drug reaction with eosinophilia and systemic
symptoms (DRESS):
» Morbiliform cutaneous eruption involving the face, trunk,
and limbs, along with fever, lymphadenopathy, hematologic
abnormalities, and organ dysfunction (especially the liver)
» Mortality ~ 10%

Aromatic AEDs, particularly CBZ, and sulfonamides
are the most common inciting agents.

Typically develops 2–6 weeks after treatment
initiation

Several formal diagnostic criteria exist
Husain Z, et al. J Am Acad Dermatol. 2013;68:693; Kardaun SH et al. Br J Dermatol. 2013;169:1071; Bocquet H
et al. Sem Cutan Med Surg. 1996;15:250; Kelly JP et al. J Clin Epidemiol. 1995;48:1099
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Cutaneous Drug Reactions:
SJS/TEN

Stevens-Johnson syndrome (SJS): less than 10%
body surface area (BSA) skin detachment

Toxic epidermal necrolysis (TEN): differs from SJS
only in severity; greater than 30% of BSA
involvement, higher mortality

Usually 1–3 weeks after drug initiation, prodromal
phase of flu-like symptoms

PHT, PHB, CBZ, and LTG are most often associated
with SJS/TEN; estimated incidence: 1–10/10,000
new users; case reports exist of other AEDs causing
SJS/TEN
Tartarone A, Lerose R. Ther Drug Monit. 2010;32:669; Mockenhaupt M et al. Neurology. 2005;64:1134; Zou LP
et al. Seizure. 2012;21:823; Duong TA et al. JAMA Dermatol. 2013;149:113; Naveen K et al. Int J Crit Illness
Injury Sci. 2012;2:44
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Cutaneous Drug Reactions:
Treatment

Prompt withdrawal of the offending agent and
initiation of aggressive supportive care remain the
mainstays of treatment

Topical corticosteroid therapy is common.

Systemic corticosteroids and other
immunosuppressive agents are controversial.

Intensive care or burn unit needed for management
of systemic complications and to optimize fluid
status, nutrition, analgesia, and infection control
Husain Z et al. J Am Acad Dermatol. 2013;68:709; Tas S, Simonart T. Dermatology. 2003;206:353
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Epilepsy in Women
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Epilepsy in Women:
Catamenial Epilepsy

Estrogen: proconvulsant

Progesterone: neuroinhibitory

One-third of women with focal epilepsy demonstrate
a catamenial pattern.
» Seizures occur at times during menstrual cycle when
estrogen level exceeds progesterone level or when levels of
either hormone are changing rapidly.

Cyclic progesterone therapy may be beneficial for a
subset of women with catamenial epilepsy.
» Less robust evidence for acetazolamide and clobazam
Pennell PB. Continuum. 2013;19:697; Herzog AG et al. Neurology. 2012;78:1959; Harden CL, Pennell PB. Lancet
Neurol. 2013;12:72
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Epilepsy in Women:
Contraception

Enzyme-inducing AEDs lead to increased
clearance—and thus decreased contraceptive
efficacy—of sex hormones.

Estrogen-containing contraceptives induce hepatic
enzymes and may decrease the serum concentration
of certain AEDs such as LTG.

Best options for women with epilepsy are long-acting
reversible contraceptives:
» Progestin implants
» Intrauterine devices (IUDs)
Davis AR et al. Epilepsia. 2011;52:243; Reimers A et al. Epilepsia. 2005;46:1414.
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Epilepsy in Women:
Risk of Congenital Malformations

~3.5% of women in their reproductive years may be
taking an AED for epilepsy or other indications (eg,
headache, pain, or a mood disorder).

AED use increases the risk of major congenital
malformations to 3%–9%, about two- to threefold
higher than the risk in the general population.

Fetal exposure to valproate has been associated with
dose-dependent impairment in cognitive abilities
during childhood.

LTG is often considered the drug of choice during
pregnancy.
Pennell PB. Continuum. 2013;19:697; Meador KJ et al. Neurology. 2008;71:1109; Harden CL et al. Neurology.
2009;73:133; Holmes LB et al. N Engl J Med. 2001;344:1132; Tomson T, Battino D. Lancet Neurol. 2012;11:803;
Meador KJ et al. Lancet Neurol. 2013;12:244
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Epilepsy in Women:
Risk of Congenital Malformations
Rates of major congenital malformations at one year
after birth in relation to exposure to AED monotherapy
Tomson T, Battino D. Lancet Neurol. 2012;11:803; Tomson T et al. Lancet Neurol. 2011;10:609
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Epilepsy in Women:
Managing Epilepsy During Pregnancy

20%–33% of women with epilepsy experience an
increase in seizure frequency during pregnancy.

Optimize seizure control before pregnancy; seizure
freedom for at least 9 months prior to pregnancy is
associated with an 84%–92% chance of remaining
seizure-free during pregnancy.

Avoid polytherapy if possible

Monitor therapeutic drug levels, especially of LTG
and LEV, monthly.

Folic acid supplementation, 0.4–5.0 mg/d
Anon. Neurology. 2006;66:354; Harden CL et al. Neurology. 2009;73:126; Pennell PB et al. Neurology.
2008;70:2130; Pennell PB, Hovinga CA. Int Rev Neurobiol. 2008;83:227; Harden CL et al. Neurology.
2009;73:142; Thomas SV. Neurol India. 2011;59:59
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Epilepsy in Patients with HIV
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Epilepsy and HIV:
Treatment Issues in Patients with HIV
Multiple considerations in
the personalized treatment
of epilepsy in patients
infected with human
immunodeficiency virus
ARV = antiretroviral therapy
AED = antiepileptic drug
From a presentation made by Gretchen L. Birbeck, MD, PhD, at AES 2013
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Epilepsy and HIV:
Drug Interactions

Concurrent use of AEDs with antiretroviral medications
(ARVs) is common, and the potential interactions
between these drug types are extensive, for example:
» Avoid saquinavir in patients on potentially arrhythmogenic
AEDs, such as ezogabine or lacosamide
» Rilpivirine and etravirine are contraindicated with CBZ,
oxcarbazepine, PHB, and PHT
» Avoid enzyme-inducing AEDs in patients taking protease
inhibitors or non-nucleoside reverse transcriptase inhibitors
» Most benzodiazepines are contraindicated with ARVs due to
the risk of prolonged sedation.

AED/ARV interactions have clinical implications for
disease progression and emergence of ARV resistance.
Birbeck GL et al. Neurology. 2012;78:139; Siddiqi O, Birbeck GL. Curr Treat Options Neurol. 2013;15:529
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Epilepsy and HIV:
Management of Epilepsy

Treatment with ARVs is recommended for all HIVpositive patients, so potential drug-drug interactions
should be anticipated before starting AEDs in an
HIV-positive patient

The AED of choice in HIV-positive patients is LEV,
due to its broad-spectrum activity, ease of use,
minimal drug interactions, and favorable side-effect
profile.
» Alternatives: pregabalin, gabapentin, lacosamide
» Valproate is also favorable because it will not induce ARV
metabolism, but its side-effect profile may be somewhat
worse than that of other therapeutic options.
Siddiqi O, Birbeck GL. Curr Treat Options Neurol. 2013;15:529
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